3.1. TFIIH and Xeroderma Pigmentosum (XP)
XP is an autosomal recessive disorder, characterized by photosensitivity
and the predisposition to skin cancer. There are many other factors,
such as thinning hair and skin, freckles, effect on eye, and even when
sunscreen is used, the likelihood of cancer is still very high from a
young age. Of the affected individuals with XP, approximately 25% could
develop neurological affects, such as acquired microcephaly, hearing
loss, cognitive impairment, impacted central nervous system and
neurodegeneration (Kraemer et al., 2022). This has come to be to known
as XP neurological disease (Y. Krasikova et al., 2021). XP can arise
from mutations occurring in several factors in the NER pathway, with
varying clinical outcomes. These complementation groups vary in severity
and rate of occurrence within the population; however, mutations within
XPA, XPC, and XPD are most common and account for more than 70% of all
XP cases (Cleaver, 2008; Martens et al., 2021).
Most XP-associated mutations in TFIIH are found in the XPD subunit,
particularly at arginine 683 (R683) in the C-terminal domain of XPD
(Taylor et al., 1997). This residue is close to one of XPD’s DNA
helicase motifs and its mutation attenuates the helicase activityin vitro (Coin et al., 2007). A number of other XP-associated
mutations have also been found, mainly in the C-terminal domain of XPD
(Table 1 ). It is generally believed that XP symptoms are
correlated with defects in the GG-NER subpathway (Fousteri &
Mullenders, 2008; Laat et al., 1999; Martens et al., 2021). The global
repair deficiency increases UV mutations and higher risk of
carcinogenesis in exposed skins cells. Hence, the clinical observations
imply that the XP-associated mutations in the XPD gene may selectively
block the GG-NER subpathway, but have less severe effect on TC-NER.
Mutations in other TFIIH subunits can also lead to XP. For example,
mutations in XPB and p8 subunits have been shown to cause XP symptoms
(Rimel & Taatjes, 2018; Singh et al., 2015).